ROSEGUINI, BRUNO PROJECT SUMMARY Peripheral arterial disease (PAD) is characterized by atherosclerotic obstruction of the arteries in the lower extremities and affects approximately 10% of individuals older than 65 years. The most common presentation of PAD is intermittent claudication (IC), defined as leg pain caused by insufficient blood flow during walking. Individuals with symptomatic PAD have severely impaired leg functioning and lose their ability to walk and perform simple functional tasks. Few non-invasive therapies currently exist to alleviate the debilitating leg symptoms that these patients experience. Exercise training is effective for restoring walking tolerance in PAD patients, but the majority of patients refuse or are unable to participate in structured exercise regimens because of comorbidities and lack of access to rehabilitation facilities. The goal of the proposed experiments is to determine the benefits of leg heat therapy (HT) on peripheral vascular endothelial function and walking tolerance in patients with PAD. This novel approach consists of custom engineered trousers, instrumented with a network of small flexible tubes that are connected to a portable water pump. Hot water is circulated through the tubes, evenly heating the buttocks, thighs and calf. This system is convenient for application in the home setting without supervision. Preliminary studies revealed that HT for 90 min evokes a robust increase in blood flow to the leg in patients with PAD. Based on these initial findings, the proposed studies will test the hypothesis that repeated increases in leg blood flow during long-term HT treatment will improve vasodilatory function of the arteries in the leg, increase oxygenation of the calf muscles and improve walking tolerance. Patients with a history of stable PAD will be randomly allocated to an HT-treated group or to a thermoneutral control group. Patients in both groups will be given similar water-circulating trousers and a portable pump, and will be asked to apply the treatment at home daily for 8 consecutive weeks. The pump given to patients in the HT group will circulate water at 48C through the trousers to raise skin temperature to approximately 39C. Patients in the control group will receive a pump that circulates water at 33C to maintain leg skin temperature at normal baseline levels. A built-in timer inside the pump and inaccessible to patients, will provide an estimate for patient compliance with the interventions. The following outcomes will be measured at baseline, at 4 and 8 weeks of treatment and at one month after the end of the intervention: (1) walking distance on a 6-min walking test, (2) peak walking time on a symptom-limited incremental treadmill test, (3) calf muscle oxygenation during exercise (near-infrared spectroscopy), (4) peak reactive hyperemia of the calf muscles (arterial spin labeling magnetic resonance imaging), (5) cutaneous microvascular function (Laser Doppler flowmetry), (6) serum levels of vasoconstrictor endothelin-1, and (7) quality of life, as assessed by responses to VascuQol and SF36 questionnaires. Since this novel intervention is non-invasive and amenable for home use, there is high potential for this work to rapidly translate into clinical practice and improve patients' lives. 1 Bruno Roseguini, Ph.D.